Micov Ana, Tomić Maja, Pecikoza Uroš, Ugrešić Nenad, Stepanović-Petrović Radica
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
Pharmacol Res. 2015 Jul;97:131-42. doi: 10.1016/j.phrs.2015.04.014. Epub 2015 May 6.
Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.
疼痛性糖尿病神经病变难以治疗。单一镇痛药往往疗效不足且耐受性差。因此，联合治疗可能特别有益，因为它可能以较少的不良反应提供最佳镇痛效果。本研究旨在研究具有镇痛特性的新型抗惊厥药左乙拉西坦与常用镇痛药（布洛芬、阿司匹林和对乙酰氨基酚）在疼痛性糖尿病神经病变小鼠模型中的相互作用类型。通过腹腔注射单次高剂量链脲佐菌素（150mg/kg）诱导C57BL/6小鼠患糖尿病。在糖尿病诱导前和诱导后三周测量热（甩尾试验）和机械（电子von Frey试验）痛觉阈值。在出现热/机械超敏反应的糖尿病小鼠中检测口服左乙拉西坦、镇痛药及其组合的抗伤害感受作用。在联合实验中，药物以单药ED50的固定剂量分数共同给药，并通过等效应线图分析确定相互作用类型。左乙拉西坦（10 - 100mg/kg）、布洛芬（2 - 50mg/kg）、阿司匹林（5 - 75mg/kg）、对乙酰氨基酚（5 - 100mg/kg）以及左乙拉西坦 - 镇痛药组合在两项试验中均对糖尿病小鼠产生了显著的、剂量依赖性的抗伤害感受作用。在甩尾试验中，等效应线图分析显示左乙拉西坦与阿司匹林/布洛芬以及对乙酰氨基酚联合使用时，两种药物的剂量分别降低了15倍和19倍。在von Frey试验中，左乙拉西坦 - 布洛芬以及左乙拉西坦 - 阿司匹林/左乙拉西坦 - 对乙酰氨基酚组合中，两种药物的剂量分别降低了约7倍和9倍。这些结果表明在疼痛性糖尿病神经病变模型中左乙拉西坦与布洛芬/阿司匹林/对乙酰氨基酚之间存在协同作用，可能为治疗疼痛性糖尿病神经病变患者提供一种有用的方法。
